Indole Alkaloids as Biased Opioid Receptor Modulators
Pharmaceuticals February 28, 2026 Oliver Grundmann, Allison Henderson
Indole alkaloids such as ibogaine and mitragynine activate μ-opioid receptors as biased full or partial agonists that recruit β-arrestin much less than non-biased agonists. Because β-arrestin recruitment is linked to adverse effects like respiratory depression, this biased activation may limit those effects. The molecular mechanism likely involves the indole structure altering the spatial orientation of amino acid residues in transmembrane regions 2 and 3 and extracellular helix 8. These naturally occurring compounds may provide a scaffold for developing new opioid modulators with an improved risk-to-benefit ratio.